Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR).
Methods and Findings
We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP–AD associations from the International Genomics of Alzheimer’s Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62–0.91]; p = 3.4 × 10−3). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10−8). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51–0.89]; p = 6.5 × 10−3), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses.
Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure—or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications—may reduce AD risk.
Robert A. Scott and colleagues use genetic instruments to identify causal associations between known risk factors and Alzheimer's disease.
Worldwide, about 44 million people have dementia, a group of brain degeneration disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. Dementia mainly affects older people, and because people are living longer, experts estimate that more than 135 million people will have dementia by 2050. The most common form of dementia, which accounts for 60%–70% of cases, is Alzheimer disease (AD). The earliest sign of AD is often increasing forgetfulness. As the disease progresses, affected individuals gradually lose the ability to look after themselves, they may become anxious or aggressive, and they may have difficulty recognizing friends and relatives. People with late stage disease may lose control of their bladder and of other physical functions. At present, there is no cure for AD, although some of its symptoms can be managed with drugs. Most people with AD are initially cared for at home by relatives and other caregivers, but many affected individuals end their days in a care home or specialist nursing home.
Why Was This Study Done?
Researchers are interested in identifying risk factors for AD, particularly modifiable risk factors, because if such risk factors exist, it might be possible to limit the predicted increase in future AD cases. Epidemiological studies (investigations that examine patterns of disease in populations) have identified several potential risk factors for AD, including hypertension (high blood pressure), obesity, smoking, and dyslipidemia (changes in how the body handles fats). However, epidemiological studies cannot prove that a specific risk factor causes AD. For example, people with hypertension might share another characteristic that causes both hypertension and AD (confounding) or AD might cause hypertension (reverse causation). Information on causality is needed to decide which risk factors to target to help prevent AD. Here, the researchers use “Mendelian randomization” to examine whether differences in several epidemiologically identified risk factors for AD have a causal impact on AD risk. In Mendelian randomization, causal associations are inferred from the effects of genetic variants (which predict levels of modifiable risk factors) on the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if hypertension actually causes AD, genetic variants that affect hypertension should be associated with an altered risk of AD.
What Did the Researchers Do and Find?
The researchers identified causal associations between potentially modifiable risk factors and AD risk by analyzing the occurrence of single nucleotide polymorphisms (SNPs, a type of gene variant) known to predict levels of each risk factor, in genetic data from 17,008 individuals with AD and 37,154 cognitively normal elderly controls collected by the International Genomics of Alzheimer’s Project. They report that genetically predicted higher systolic blood pressure (SBP; the pressure exerted on the inside of large blood vessels when the heart is pumping out blood) was associated with lower AD risk (and with a higher probability of taking antihypertensive medication). Predicted smoking quantity was also associated with lower AD risk, but there was no evidence of causal associations between any of the other risk factors investigated and AD risk.
What Do These Findings Mean?
In contrast to some epidemiological studies, these findings suggest that hypertension is associated with lower AD risk. However, because genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication, it could be that exposure to such drugs, rather than having hypertension, reduces AD risk. Like all Mendelian randomization studies, the reliability of these findings depends on the validity of several assumptions made by the researchers and on the ability of the SNPs used in the analyses to explain variations in exposure to the various risk factors. Moreover, because all the participants in the International Genomics of Alzheimer’s Project are of European ancestry, these findings may not be valid for other ethnic groups. Given that hypertension is a risk factor for cardiovascular disease, the researchers do not advocate raising blood pressure as a measure to prevent AD (neither do they advocate that people smoke more cigarettes to lower AD risk). Rather, given the strong association between higher SBP gene scores and the probability of exposure to antihypertensive treatment, they suggest that the possibility that antihypertensive drugs might reduce AD risk independently of their effects on blood pressure should be investigated as a priority.
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001841.
The UK National Health Service Choices website provides information (including personal stories) about Alzheimer disease
The UK not-for-profit organization Alzheimer’s Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer disease
The US not-for-profit organization Alzheimer’s Association also provides information for patients and carers about dementia and personal stories about dementia
Alzheimer’s Disease International is the federation of Alzheimer disease associations around the world; it provides links to individual Alzheimer associations, information about dementia, and links to world Alzheimer reports
MedlinePlus provides links to additional resources about Alzheimer disease (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
A PLOS Medicine Research Article by Proitsi et al. describes a Mendelian randomization study that looked for a causal association between dyslipidemia and Alzheimer disease